Pharmacokinetics of amantadine in children with impaired consciousness due to acquired brain injury: preliminary findings using a sparse-sampling technique.

OBJECTIVE

To evaluate the pharmacokinetics of amantadine in children with impaired consciousness from acquired brain injury.

DESIGN

Randomized, double-blind, placebo-controlled, crossover study with sparse sampling for pharmacokinetics.

SETTING

Tertiary care pediatric hospital.

PARTICIPANTS

Children, ages 6-18 years, with impaired consciousness 5-10 weeks after acquired brain injury.

METHODS

Subjects received amantadine for 3 weeks. Subjects were randomized to placebo or amantadine 4 mg/kg/day for 7 days followed by 6 mg/kg/day for 14 days. Crossover was after a 7-day washout period.

MAIN OUTCOME MEASURES

The Coma/Near-Coma Scale and Coma Recovery Scale-Revised were done 3 times per week to evaluate arousal and consciousness. Plasma concentrations of amantadine were determined for pharmacokinetic parameter estimation and evaluation of the exposure-response relationship. Adverse events were monitored.

RESULTS

Nine subjects met the final inclusion and exclusion criteria, 7 of whom agreed to participate. Five subjects completed both arms of the study. Amantadine total body clearance was 0.17 L/h/kg with a half-life of 13.9 hours. Higher exposure of amantadine (average concentration of amantadine during 6 mg/kg/day > 1.5 mg/L) may be associated with better recovery of consciousness.

CONCLUSIONS

Amantadine was well-tolerated in children with acquired brain injury and demonstrates pharmacokinetics similar to those reported for healthy young adults. Based on the preliminary data, higher dosing may be considered in the setting of brain injury.